PROJECT 1 SUMMARY Men of African descent have the highest rates of prostate cancer incidence and mortality compared with all other ethnic and racial groups. In African American men, the age-adjusted incidence is 251.9 per 100,000 compared with 173.5 per 100,000 in men of European descent. For men living in African countries, these rates are of even more concern, with a three-fold higher mortality compared with patients in the United States and Europe. This trend has been partly attributed to socio-economic factors, inadequate access to healthcare, and the known differences in genetic factors. Recently, our group has studied genomic biomarkers in men with aggressive prostate cancer, and reported that the expression of a subset of these biomarkers was race-specific. Our central hypothesis is that aggressive prostate cancer in African American men may arise from distinct molecular subtype(s) as such respond to treatment differently. However, there are no biomarker tools to identify this subset of at-risk African American men with aggressive disease because most of these biomarkers have been mainly derived from tissue from men of European origin. To this end, our goal is to develop a race-specific biomarker-driven tool that can: 1) identify the subset of African American patients origin with aggressive disease and ?fast track? these patients to more aggressive treatment schedules; and 2) provide actionable targets to develop new effective treatments for this high risk population. To achieve this goal, we propose the following specific aims: first, we will characterize the genomic risk profile of prostate cancer in highly screened US men (of European and African heritage) versus less-screened native African men living in West Africa; second, we will develop and independently validate a biomarker signature that can predict aggressive prostate cancer in African American men. A third future aim is to implement and prospectively validate biomarker-based risk-adapted treatments within ongoing clinical studies. Our project uses innovative methods to conduct this comparative evaluation, which has the potential to develop predictive molecular signatures that can help identify African American men with aggressive prostate cancer who may respond better to more intensified treatment schedules or other novel treatments. In addition, validating the putative biomarkers in a cohort of native African men with prostate cancer will enrich for true biomarkers of greater sensitivity for detecting aggressive phenotypes in men of African origin. The ability to identify a subset of men who harbor aggressive disease will improve clinical trial design, and open avenues for testing new or optimized treatments, thus improving outcomes in this high risk patient population.